The risk of premature cardiac contractions (PAC/PVC) related to caffeine consumption among healthcare workers: A comprehensive review

Abstract Background and Aims Premature atrial contractions (PACs) and premature ventricular contractions (PVCs) are ectopic heart rhythm disorders with implications for cardiovascular health. This study explores the relationship between caffeine consumption and the risk of PACs and PVCs, with a focus on healthcare workers, such as doctors, nurses, pharmacists, and midwives, who often rely on caffeine to combat fatigue, especially during night shifts. Methods A thorough review was conducted through PubMed, Scopus, Google Scholar, and Web of Science, utilizing a combination of MeSH terms and keywords. Studies examining the link between caffeine consumption and PACs and PVCs, particularly in healthcare workers, were included. Results We found that caffeine shows various effects based on dosage and can impact arrhythmia risk. Individuals working long shifts, including healthcare professionals, are prone to increased caffeine intake, leading to higher cardiovascular risk. To mitigate these risks, tailored guidelines for caffeine consumption, flexible shift scheduling, and mental health support services are recommended. Promoting caffeine alternatives within healthcare institutions can be beneficial. Conclusion Although caffeine may have potential benefits, its drawbacks, particularly concerning cardiovascular health, may surpass its advantages, especially when consumed in high doses. A multidisciplinary approach is crucial for healthcare workers’ well‐being and quality of patient care. Further research is required to refine and support these recommendations.


| INTRODUCTION 1.| PAC and PVC
Premature cardiac contractions, also known as atrial and ventricular ectopic beats, are ectopic heart rhythm disorders in the general population. 1 They arise when ectopic impulses from the muscle fiber or fibers within the ventricles or atriums occur independently of the physiological pacemakers. 2 Based on the origin of these ectopic beats, we classified them as premature atrial contractions (PACs) and premature ventricular contractions (PVCs). 3A correlation exists between frequent PACs and PVCs and a higher risk of cardiovascular events, morbidity, and mortality. 3Recent studies have shown that recurrent PACs are associated with increased atrial fibrillation, ischemic stroke, transient ischemic attack, and mortality in older patients without a history of AF. 4 PACs may result from non-cardiac (chronic and acute pulmonary disease, chronic renal failure, neurological disorders) or cardiac diseases (acute myocardial infarction, coronary artery disease, valvular heart diseases, and cardiomyopathy) As well as behavioral/ other (like alcohol, theophylline, caffeine, smoking, and thyroid conditions). 2ssible causes of PVCs are categorized as cardiac, pulmonary, endocrinopathies, and behavioral/other factors.Cardiac causes include heart failure, acute myocardial infarction, hypertension with left ventricular hypertrophy, hypertrophic cardiomyopathy, congenital heart disease, and idiopathic ventricular tachycardia.Pulmonary causes encompass COPD, sleep apnea, pulmonary hypertension, and other pulmonary diseases.Endocrinopathies involve thyroid, adrenal, and gonadal abnormalities.Behavioral and other factors consist of nicotine, caffeine, alcohol, sympathomimetic agents (e.g., beta-agonists, antihistamines), and illicit drugs (e.g., cocaine, amphetamines). 2 The different etiologies of PAC and PVC are shown in Table 1.

| Caffeine
Caffeine is a chemical compound belonging to the methylxanthines group that acts as a stimulant for the central nervous system. 5In healthy individuals, the mean half-life of caffeine in plasma is about 4-5 h, ranging from 2 to 10 h. 6Caffeine's mechanism involves blocking adenosine receptors, boosting dopamine release, and increasing alertness.It also elevates cAMP levels, leading to heightened stimulation.Additionally, it opens ion channels in muscles, releasing calcium ions for improved muscle function. 7Plants like Camellia Sinensis, Khat, Cola Tree, Guayusa, Coffee, Guarana, Cacao Tree, and Cassina Tree contain caffeine in their leaves, seeds, and fruits.10] Caffeine functions as an adenosine receptor antagonist with a primary focus on the A1 and A2A receptors.This interaction leads to physiological responses by partially blocking these members of the adenosine receptor family. 11These responses are closely intertwined with various brain functions related to sleep regulation, wakefulness, and cognitive processes.3][14] In addition, caffeine stimulates metabolic activity while reducing the sensations of tiredness and hunger, ultimately supporting the assertion that caffeine enhances overall performance. 15It also has positive inotropic and chronotropic effects on the cardiovascular system. 1,16Moreover, caffeine increases norepinephrine and epinephrine plasma levels due to its sympathomimetic effects; consequently, it likely causes an increase in cardiac ectopy. 1,17The physiological effects of caffeine on the human body are illustrated in Figure 1.
According to the guidelines, adults should limit their daily caffeine intake to 180 mg to maintain alertness and prevent health risks. 1,8commended caffeine doses, based on body weight, are classified as low (3 mg/kg), moderate (5-6 mg/kg), and high (≥9 mg/kg).Up to 6 mg/kg generally has no serious adverse effects, while higher doses may lead to issues like decreased reaction time and insomnia.Athletes may require higher doses for performance enhancement.However, doses ≥9 mg/kg may not improve performance and could cause overstimulation, especially in hypersensitive individuals.Daily doses exceeding 2000 mg pose serious health risks, including hypertension and cardiac issues. 18Also, it can cause dependence.Abruptly stopping excessive caffeine can result in withdrawal symptoms, including headaches, palpitations, exhaustion, difficulty concentrating, and discomfort. 19fferent caffeine-containing drinks have different caffeine concentrations, as shown in Table 2.The numbers in the table are not exact and may vary depending on the differences in processing and brewing.
Having information on caffeine concentration in different drinks reduces the risk of over-consumption and poisoning (Staff 2022). 20

| Caffeine and the risk of PAC and PVC
According to the guidelines of the American Heart Association on the management of patients with arrhythmia, they are always advised to avoid caffeine consumption. 1,21Nonetheless, the currently available data do not provide strong evidence for the association between caffeine and PAC or PVC in the general population.[24] 1.4 | Caffeine and the risk of PACs and PVCs in healthcare workers Caffeine has effects on vitality, alertness, fatigue, and cognitive performance. 25Previous research suggests that caffeine can help shift workers prevent fatigue. 26Therefore, caffeine consumption has increased among shift workers, particularly among EMS and healthcare workers, in an attempt to reduce fatigue and improve performance. 25e to a lack of data on the risk of PACs and PVCs associated with caffeine consumption among healthcare workers, we aimed to investigate this issue and recommend some critical points to reduce the risk of arrhythmia among healthcare professionals.Concerning the novelty of this study, we found no recent similar review studies exploring the link between caffeine consumption and the occurrence of PAC and PVC in healthcare workers.

| METHODS
We conducted an extensive database search across PubMed, Scopus, Google Scholar, and Web of Science during 2 months (October and November 2023) using a combination of MeSH terms and keywords PAC within a day. 278][29] Ethnicity and educational status do not significantly impact the frequency of PAC.There is conflicting evidence regarding obesity and gender.
Factors associated with PVC occurrence are shown in Figure 2.

| PVC
Many studies have reported different rates of PVC in different populations.It is believable that everyone experiences PVC in their lifetime at different frequencies. 30In a recent review by Klewer et al., 31 the prevalence of PVC in the general population is 3%-20%, mainly diagnosed in palpitation check-ups or incidentally in routine health check-ups.3][34][35] Factors associated with the occurrence of PVC are shown in Figure 3.
The associations between various factors and PACs and PVCs are summarized in Table 3.
Factors associated with the occurrence of PAC.Blue circles elevate the possibility of PAC while red circles decrease the possibility.PAC, premature atrial contraction.

| Caffeine
In the United States, 85% of the population consumes at least one caffeinated beverage daily.The average daily caffeine intake for all ages is 165 mg.Individuals aged 50-64 have the highest intake of 226 mg/day.The 90th percentile intake is 380 mg/day.Coffee is the main source of caffeine across all age groups, while younger individuals (<18 years) get a higher percentage of caffeine from carbonated soft drinks and tea. 36They also noted that in older ages, caffeine consumption was more common, and coffee was the main source of caffeine.Two studies by Mitchell et al. 36 and Fulgoni et al. 37 reported a similar prevalence (89% and 85%, respectively) of caffeine consumption in the US population.Additionally, Fulgoni et al. 37 reported that the highest amount of caffeine consumption was in men aged 31-50 years, whereas the lowest amount was in women aged 19-30.The daily intake of caffeine per body weight was similar in men and women.A higher caffeine intake (≥400 mg/day) was more commonly observed in men.Caffeine consumption was more prevalent in single students, first-year students, and those with higher grade point averages, and caffeinated food and beverages were more commonly consumed during exams and stressful times.
Furthermore, the prevalence of high BMI was higher in the caffeineconsuming group.According to the study by Lieberman et al., 38 age and ethnicity were the most associated variables with caffeine intake, smoking, working hours, and daily calorie intake being other associated factors. 37,38They also reported that caffeine consumption was not significantly related to physical activity, economic status, education, or employment status.White non-Hispanics and the middle-aged group (50-54 years) had the highest caffeine consumption.Overall, caffeine consumption is more common among adolescents, smokers, and those of white ethnicity.

| Caffeine and the risk of PAC and PVC
Marcus et al. 39 conducted a trial that compared the prevalence of PAC and PVC between caffeine consumers and non-consumers.They concluded that caffeine consumption and the prevalence of daily PAC were not related; however, higher caffeine intake was associated with a higher risk of PVC.Dixit et al. 1  that there was no significant relationship between caffeine and PAC, but they also noted that PVC and caffeine intake are not related.In a multicenter study by Kim et al., 40 a higher amount of habitual caffeine intake led to a lower risk of cardiac arrhythmia.

| CHALLENGES
Healthcare professionals facing extended shift hours and minimal room for error often experience significant demands, which can result in fatigue, disrupted sleep, and an increased likelihood of making mistakes. 41To address these challenges, many healthcare staff tend to consume caffeine as a solution for managing tiredness, coping with the stress associated with their jobs, and enhancing their alertnessall essential factors in their work environments. 42,43Additionally, individuals working night shifts intentionally rely on caffeine to stay awake and remain sharp during their demanding duties. 44ke many other drugs and medications, caffeine has a range of potential side effects.These effects can span from relatively minor discomfort to potentially quite severe, and in some rare cases, even life-threatening.The severity of these adverse effects is often linked to both the amount of caffeine consumed and individual sensitivity to the substance. 45Common side effects include anxiety, restlessness, fidgeting, insomnia, facial flushing, increased urination, muscle twitches or tremors, irritability, agitation, and elevated and even irregular heart rate. 11rthermore, caffeine can stimulate the body's stress response system, resulting in increased release of stress hormones such as glucocorticoids and catecholamines, which in turn can lead to an increase in blood pressure.Therefore, caffeine consumption during stressful periods can extend and intensify the body's stress response, affecting both blood pressure and the release of stress hormones.
This insight could have vital implications for individuals who are particularly sensitive to caffeine, especially those at risk of developing hypertension. 14ditionally, in individuals with heightened sensitivity to caffeine, consuming high doses can result in a set of symptoms collectively known as 'caffeinism'.These symptoms may include increased anxiety, restlessness, nervousness, dysphoria, difficulties in falling asleep, and a tendency for thoughts and expressions to become disorganized and erratic. 46ong the limited number of studies highlighting a connection between coffee consumption and heart rhythm irregularities, one notable report revealed that a higher daily coffee intake was associated with a greater probability of PVCs observed during a 2min electrocardiogram recording. 30Moreover, an increased occurrence of PAC was found to be a predictor of the development of new-onset atrial fibrillation.Remarkably, a greater prevalence of PVC was associated with an increased risk of heart failure. 39A noteworthy aspect in this context is that certain subgroups, particularly those with specific genetic variations such as CYP1A2 or COMT variants, may be more prone to the cardiovascular effects of caffeine. 47veral studies have consistently validated the safety of caffeine consumption at typical daily usage levels.Nevertheless, exceeding a specific caffeine threshold, approximately estimated at 1.2 g, can lead to undesirable side effects.These repercussions encompass symptoms such as an accelerated heart rate, irregular cardiac rhythms, altered mental function, and even seizures.In the most severe cases, excessively high caffeine doses, typically falling within the range of 10-14 g, have been associated with life-threatening outcomes. 11cessive caffeine intake appears to disrupt the natural electrical activity of the heart, resulting in the emergence of various arrhythmias.Therefore, individuals should consume moderate and measured coffee consumption to prevent the risk of these adverse consequences. 39,48w individuals respond to caffeine can vary considerably, and this diversity is strongly shaped by the process of habituation and tolerance that develops in response to many of the physiological effects of caffeine.Those who are not accustomed to consuming caffeine regularly tend to avoid developing this habituation or The relationship between different factors and PAC and PVC.
Factor Association with PACs tolerance.Consequently, they often feel the effects of caffeine even when their dietary intake is low. 49reover, the diversity in how caffeine affects individuals can be attributed to a range of genetic factors.Specific genetic variations, known as polymorphisms, have the potential to impact both the manner in which caffeine is metabolized in the body and its effects mediated by receptors. 45In addition, tolerance can develop as a response to the increased levels of tension, anxiety, and jitteriness that are often linked to the consumption of caffeine. 50e issue of caffeine dependence is a matter of significant concern.While caffeine is recognized as a mild stimulant of the central nervous system, preclinical studies have indicated that it does not trigger dopaminergic transmission in the nucleus accumbens shell, a distinctive characteristic observed in substances associated with addiction.Sudden cessation of caffeine intake can result in mild and transient withdrawal symptoms.These typically begin after 12-24 h of abstinence, peak around 20-48 h, and may persist for up to a week.These symptoms include headaches, fatigue, drowsiness, irritability, depressed mood, and anxiety.However, these withdrawal symptoms can be prevented by gradually reducing caffeine consumption rather than abruptly discontinuing it.In cases where symptoms do manifest, they can be quickly relieved by caffeine readministration.Importantly, caffeine withdrawal symptoms may vary significantly among individuals, but they are typically short-lived and not harmful. 11,51ffeine acts as a "reinforcer," easing withdrawal discomfort, but how it does so is not fully understood.Tea and coffee contain sufficient caffeine to serve as reinforcers; people often rely on these beverages during withdrawal, forming a cycle of dependency.Even a small amount, like 25-50 mg of caffeine per cup of coffee, can offer relief. 46,52

| RECOMMENDATIONS
Caffeine's effects depend on the dosage, and high doses can impact cardiac contractility and increase the risk of arrhythmias. 53,54althcare workers should prioritize following tailored guidelines that promote the safe consumption of caffeine and ensure that they do not exceed the recommended limits.The recommended daily caffeine limit for adults (aged 18 and older) is approximately 400 mg, which does not result in negative consequences. 40,55ng work shifts cause sleep deprivation, affecting healthcare workers who often experience circadian misalignment and sleep inertia.7][58] This can result in increased caffeine intake among healthcare workers with long shifts.
Therefore, healthcare institutions should explore the adoption of flexible shift scheduling and work-life balance initiatives.This move aims to decrease the dependence on caffeine among healthcare workers and, consequently, enhance the quality of patient care they provide.
Also, in a recent study, researchers examined the impact of substituting caffeinated or decaffeinated coffee with a noncaffeinated coffee alternative on adverse caffeine effects.Findings suggest that individuals experiencing caffeine-related problems, such as functional dyspepsia, may find relief by transitioning to a coffee substitute. 59Therefore, promoting the use of caffeine substitutes or alternatives and facilitating their accessibility within healthcare institutions may be a favorable approach.
Some studies have shown that in cases without structural heart disease, heightened stress and anxiety levels are associated with an increase in catecholamines, which in turn can lead to a more frequent occurrence of ectopic heartbeats in both ventricular and atrial arrhythmias. 60,61On the other hand, caffeine may induce anxiety symptoms in the general population, especially at high doses.These effects tend to be more prominent in sensitive individuals, including those with panic disorder, depression, and social anxiety disorder. 62,63Also, doctors often prioritize their altruistic and professional motives, potentially neglecting their well-being.The impact on mental health, particularly anxiety disorders, is a notable concern in the context of hospital medicine. 64Given that anxiety can contribute to an increased occurrence of ectopic heartbeats, these individuals may face a heightened risk associated with the consumption of excessive caffeine.Therefore, the implementation of stress management programs and mental health support services for healthcare workers can be advantageous in this context.
Ultimately, there is a need for a multidisciplinary approach to reduce caffeine-related PACs and PVCs in healthcare workers, which is crucial for their well-being and the quality of patient care.
Implementing these recommendations may substantially enhance the health and productivity of healthcare workers, yet further scientific investigation is warranted to support and refine these measures.

ACKNOWLEDGMENTS
We would like to express our sincere gratitude to all those who contributed to the completion of this research, particularly acknowledging the collaborative spirit and equal contribution of all team ABDOLMALEKI ET AL.
| 7 of 9 members in the original draft preparation and review process.This research would not have been possible without the collective efforts and dedication of each contributor.
also concluded F I G U R E 3 Factors associated with the occurrence of PVC.Blue circles elevate the possibility of PAC while red circles decrease the possibility.PAC, premature atrial contraction; PVC, premature ventricular contraction.

1
Etiologies of PAC and PVC.
Cardiac."The inclusion criteria were as follows: (1) All types of studies exploring the link between caffeine and PVC/PAC; (2) studies evaluating caffeine consumption in healthcare professionals.